Use of a compound in the treatment of sleep disorders and the like, in providing refreshedness on waking and a method for the treatment of grogginess therewith

ABSTRACT

There is disclosed the use of triprolidine for enabling an individual to wake refreshed after sleep and the method of treating an individual with triprolidine. Use of triprolidine as active ingredient in the manufacture of a composition for the treatment of sleep disorders is also described. A method of treating sleep of a person suffering from a sleep disorder, which method comprises administration of an effective dose of triprolidine as active ingredient to such a person is also described. The triprolidine is administered shortly before a person wishes to fall asleep, preferably orally and most commonly in the form of a tablet containing up to 20 mg, e.g. 0.1 mg, 1.25 mg or 2.5 mg, of the active ingredient. The triprolidine is also effective in enabling an individual to sleep more easily.

The invention relates to a novel use of a known compound, in particularto the use of that compound in the treatment of sleep disordersexperienced by a person, whatever the cause of those disorders

The present invention also relates to a method for the treatment orprevention of grogginess, drowsiness or lethargy on waking from sleep,to the use of triprolidine as an aid to waking refreshed and to the useof triprolidine as both a sleep aid and a means to wake refreshedthereafter.

Although much is known about the use of various pharmaceutical sleepingformulations as aids to sleeping, little has been published about thepossibility of a sleep aid enabling an individual to wake refreshed asopposed to merely experiencing degrees of hangover effects such asgrogginess, drowsiness, lethargy, etc.

Many people experience, either on an occasional or chronic basis,difficulty in achieving a satisfactory amount of sleep. Such a problemmay be attributable to external factors, such as factors causing stressor anxiety, to excessive use or misuse of stimulants (such as caffeine)or depressants (e.g. alcohol), or to temporary disturbance of theperson's lifestyle, e.g. occasioned by shift-working or long-haul travelthrough different timezones. Difficulty in sleeping may also be causedby chronic pain, e.g. pain caused by sciatica etc. Whatever the cause,the condition may be generally considered to be a sleep disorder and maycommonly be referred to as “insomnia”. It may manifest as difficulty infalling asleep and/or wakefulness during the desired period of sleep,leading to a shortened duration of sleep and/or disruption of the normalpattern of sleep.

The result of these difficulties will commonly be fatigue during theperiod of wakefulness, which may itself lead to stress and exacerbatethe problem.

Various products are available to assist a user in overcoming problemsof the type described above. Such products, commonly called “sleepingpills” may, however, suffer from disadvantageous side-effects. Forexample, while the products may be effective in sending a user to sleep,their effect may be of short duration, resulting in premature wakening.In other cases, the user may achieve the desired length of sleep but mayawake with feelings of grogginess (a “hangover” effect). Such productsmay also be addictive. Tolerance may also develop to the drug whichresults in a decrease in effectiveness.

In other circumstances, a person may not suffer from sleep disorders assuch, but may simply wish to achieve a particularly good night's sleep.In other words, the use of such products may be elective, rather thannecessitated by a clinical need.

In addition to this well documented problem, many people also experiencedifficulties on waking such as grogginess, lethargy and drowsiness;difficulty in becoming fully alert and an absence of feeling refreshed.These phenomena are not necessarily linked to the number of hours sleepor always encountered as a result of drugs taken prior to sleep such asalcohol, medication, etc. Furthermore, individuals encounteringtiredness during waking hours and other individuals having difficultywith insomnia resort to sleep aids in an attempt to increase or improvesleeptime rest. Nevertheless, it is also well documented that a negativeside effect of sleep aids can also be an increased feeling of grogginesson waking.

Triprolidine,(E)-2-[1-(4-methylphenyl-3-(1-pyrrolidinyl)-1-propenyl]pyridine, is afirst generation anti-histamine and has been marketed alone and, incombination with pseudoephedrine (a decongestant), for the treatment ofallergic rhinitis. Triprolidine is known to have sedative effects andhas been shown to have an adverse effect on the cognitive functions ofusers. These are undesirable side-effects for an anti-histamine and mayaccount for the limited extent to which triprolidine has been used inclinical practice. More recently-developed, second generationanti-histamines are less prone to such side effects, and most recentstudies involving triprolidine have used that compound as a positivecontrol against which the more modern anti-histamine compounds have beencompared. Such studies have generally been conducted using healthyvolunteers following day time dosing, rather than persons suffering fromany form of sleep disorder, and have been concerned with the effects ofthe drug on day-time performance.

One study is known to have investigated the effect of triprolidine(amongst other anti-histamines) on sleep directly (Nicolson et al,Neuropharmacology (1985) 24, 3, 245-250). In that study single doses oftriprolidine (10 mg or 20 mg sustained release) were given at bedtime tovolunteers. It was found that triprolidine did not significantly alter“sleep onset latency” (i.e. the time required to fall asleep) comparedwith placebo. It was also found that, compared with placebo,triprolidine had no effect on wakefulness during sleep or total sleeptime.

It has now been found that, contrary to what might have been expected inthe light of previous studies, triprolidine can be used for inducing,prolonging or enhancing sleep, and that its use is accompanied byimportant benefits in comparison with other compounds known for thispurpose that could not have been predicted.

It has also been found that triprolidine surprisingly increases thelevel of refreshedness felt upon waking if taken before sleeping.Advantageously, this effect is observed whilst triprolidine also acts asa sleep aid in facilitating the onset of stage 1 sleep and whilstenhancing sleep.

The increased level of refreshedness felt upon waking after takingtriprolidine prior to sleeping was not expected and there has been noknown disclosure of such an effect previously encountered.

According to a first aspect of the present invention there is providedthe use of triprolidine or a salt or hydrate thereof as activeingredient of an aid to waking refreshed after sleeping.

According to a second aspect of the present invention there is providedthe use of triprolidine or a salt or hydrate thereof as activeingredient in the preparation of a composition for enabling anindividual to wake refreshed after sleeping.

According to a third aspect of the present invention there is providedthe use of triprolidine or a salt or hydrate thereof as activeingredient in the preparation of a medicament for enabling an individualto wake refreshed after sleeping.

According to a fourth aspect of the present invention there is providedthe use of triprolidine or a salt or hydrate thereof in the preparationof a sleep aid which also enables an individual to wake refreshed aftersleeping.

According to a fifth aspect of the present invention there is providedthe use of triprolidine or a salt or hydrate thereof as activeingredient of a sleep aid which also enables an individual to wakerefreshed after sleeping.

According to a sixth aspect of the present invention there is providedthe use of triprolidine or a salt or hydrate thereof as activeingredient in the preparation of a medicament for the treatment orprevention of a sleep disorder which also enables an individual to wakerefreshed after sleeping.

According to a seventh aspect of the present invention there is provideda method for the treatment or prevention of grogginess, drowsiness orlethargy on waking from sleep in a mammal comprising the administrationto the mammal in need thereof of a non-toxic effective dose oftriprolidine or a salt or hydrate thereof prior to the desired sleepingtime.

According to an eighth aspect of the present invention there is provideda method for enabling an individual to wake refreshed after sleepingcomprising the administration to the individual in need thereof andprior to the desired sleeping time of a non-toxic effective dose oftriprolidine or a salt or hydrate thereof.

According to a ninth aspect of the present invention there is provided amethod for aiding an individual's sleep and for also enabling theindividual to subsequently wake refreshed after sleeping comprising theadministration to the individual in need thereof and prior to thedesired sleeping time of a non-toxic effective dose of triprolidine or asalt or hydrate thereof.

According to a tenth aspect of the present invention there is provided awaking refreshed aid comprising triprolidine or a salt or hydratethereof as active ingredient in association with a pharmaceuticallyacceptable carrier therefor and instructions for administration thereofat or just before the desired sleeping time.

According to an eleventh aspect of the present invention there isprovided a pharmaceutical formulation for the treatment or prevention ofgrogginess, drowsiness or lethargy on waking after sleeping, comprisingtriprolidine or a salt or hydrate thereof as active ingredient inassociation with a pharmaceutically acceptable carrier therefor andinstructions for administration thereof at or just before the desiredsleeping time.

According to a twelfth aspect of the present invention there is provideda pharmaceutical formulation for enabling an individual to wake morerefreshed after sleeping, comprising triprolidine or a salt or hydratethereof as active ingredient in association with a pharmaceuticallyacceptable carrier therefor and instructions for administration thereofat or just before the desired sleeping time.

According to a thirteenth aspect of the present invention there isprovided a method of treating sleep of a person suffering from a sleepdisorder, which method comprises administration of an effective dose oftriprolidine as active ingredient to such a person.

According to a fourteenth aspect of the present invention, there isprovided the use of triprolidine as active ingredient in the manufactureof a composition for the treatment of sleep disorders.

According to a fifteenth aspect of the invention, there is provided amethod for inducing, prolonging and/or enhancing sleep, which methodcomprises administration of an effective dose of triprolidine as activeingredient to a person desirous of achieving sleep.

In a related aspect of the invention, there is provided the use oftriprolidine as active ingredient in the manufacture of a compositionfor inducing, prolonging and/or enhancing sleep.

It will also be understood that the term “inducing, prolonging and/orenhancing sleep” may encompass the treatment of a sleep disorder, i.e. adifficulty in achieving satisfactory sleep due to some internal orexternal factor, e.g. pain, stress or anxiety, misuse of stimulants ordepressants, or temporary disturbance of lifestyle. Alternatively, itmay encompass elective desires on the part of a user to achieve aparticularly beneficial period of sleep. Such a desire may, forinstance, arise in anticipation of important events the following dayfor which a person may wish to be fully alert and refreshed. In anyevent, the term “sleep disorder” as used herein should be taken toindependently include any one or more of the foregoing and,specifically, any objective or subjective difficulty in an individual inany one or more of the following:—

-   -   getting to sleep, especially stage 1 sleep    -   staying asleep    -   sleeping well    -   waking refreshed    -   waking alert    -   keeping awake    -   keeping alert    -   keeping refreshed    -   performing well the next day

The present invention also extends to the use of triprolidine as a sleepaid. By definition, a sleep aid extends to use by a healthy individualwho elects for a sleep aid, for example, before an important event. Theterm “sleep aid” as used herein includes any one or more of thefollowing benefits:—

-   -   faster onset to stage 1 sleep    -   increasing duration of sleep periods    -   decreasing the number and duration of awakenings    -   increasing total duration of sleep    -   increasing probability of sleeping well    -   improving insomnia, especially chronic or mild-moderate insomnia    -   decreasing disturbances during sleeptime    -   improving quality of sleep,    -   as determined by any standard or known subjective or objective        measures, for instance the Karolinska scale, Loughborough sleep        log or actimetry.

The method of aiding an individual's sleep typically indicates aiding inthe sense of providing any one or more of the above mentioned benefits.

Typically, the percentage of individuals who, after taking a dose oftriprolidine before sleeptime, wake refreshed after sleeping is in therange 1-100%, more typically, 5-70%, most typically 10-35%. Anespecially typical range as aforesaid is 15-30% or even more especially20-30%. Typically, by the terms “waking refreshed” or “wake refreshed”is meant that an individual felt at least refreshed on waking,preferably, the terms are defined as the individual felt very refreshedor refreshed in accordance with the Loughborough sleep log.

Typically, the percentage of individuals who, after taking a dose oftriprolidine before sleeptime, wake refreshed after sleeping is morethan 2%, more typically, more than 8% and most typically, more than 15%.An especially typical level as aforesaid is more than 18% or even moreespecially more than 20%.

By the term sleeping as referred to herein is meant an individual in atleast Stage 1 sleep. By the term sleeptime as referred to herein ismeant the time an individual desires to go to sleep.

Typically, the percentage of individuals who, after taking a dose oftriprolidine before sleeptime, felt alert after sleeping is in the range1-100%, more typically, 5-60%, most typically 10-30%. An especiallytypical range as aforesaid is 15-30% or even more especially 20-30%.

Typically, the percentage of individuals who, after taking a dose oftriprolidine before sleeptime, felt alert after sleeping is more than2%, more typically, more than 8%, most typically more than 12%. Anespecially typical level as aforesaid is more than 16%.

By the term felt alert is meant that an individual felt at least alerton waking. Preferably, the term is defined as the individual felt alert,very alert or extremely alert in accordance with the Karolinska 9-pointscale.

Typically, the percentage of individuals who, after taking a dose oftriprolidine before sleeptime, felt sleepy on waking is less than 25%,more typically, less than 20%, most typically less than 15%. Anespecially typical level as aforesaid is less than 14% or even moreespecially a mean level of less than 12%.

By the term felt sleepy is meant that an individual felt sleepy onwaking. Preferably, the term is defined as the individual felt sleepy orvery sleepy in accordance with points 8 or 9 of the Karolinska 9-pointscale.

Preferably, in use of the present invention as defined herein, the meansubjective feeling of refreshedness after waking as, for instance,determined on a 5 point scale, e.g. by the morning log of theLoughborough sleep log, is increased by at least 2%, more typically, byat least 4%, most typically, by at least 5%, as compared with anequivalent dose of placebo.

Typically, in use of the present invention as defined herein, the meansubjective feeling of refreshedness after waking as for instance,determined on a 5 point scale, e.g. by the morning log of theLoughborough sleep log, is increased by between 1-20%, more typically,1-15%, most typically 2-10% as compared with an equivalent dose ofplacebo.

The degree of refreshedness and quality of sleep may be determined bythe “morning” log of the Loughborough sleep log with the highest degreeof refreshedness or quality of sleep being represented as 1 and thelowest being represented as 5. Accordingly, the percentage increase inrefreshedness or quality of sleep is measured in this context by thedecrease in the mean refreshedness or quality of sleep.

Preferably, by the use of the present invention, the response ofawakening very refreshed or refreshed, as determined, for instance, bythe morning log of the Loughborough sleep log, is improved by at least20%, more preferably, by at least, 30%, most preferably by at least 40%,as compared with an equivalent dose of placebo.

Typically, by the use of the present invention, the response ofawakening very refreshed or refreshed, as determined, for instance, inaccordance with the morning log of the Loughborough sleep log isimproved by between 5% and 100%, more typically, by between 10% and 80%,most typically by between 20% and 60%, especially 40-55% and moreespecially 40-45% as compared with an equivalent dose of placebo.

Preferably, by the use of the present invention, the response of feelingextremely alert, very alert or alert, as determined, for instance, inaccordance with the Karolinska 9-point scale, is improved by at least2%, more preferably, by at least, 5%, most preferably by at least 10%,as compared with an equivalent dose of placebo.

Typically, by the use of the present invention, the response of feelingextremely alert, very alert or alert, as determined, for instance, inaccordance with the Karolinska 9 point scale, is improved by between 1%and 40%, more typically, by between 2% and 30%, most typically bybetween 10% and 20%, as compared with an equivalent dose of placebo. Anespecially preferred range is 10-30%.

Preferably, by the use of the present invention, the response of feelingsleepy and needing to make some effort to stay awake or very sleepy, asdetermined, for instance, in accordance with points 8 and 9 of theKarolinska 9 point scale, is improved (ie. decreased) by at least 2%,more preferably, by at least, 4%, most preferably, by at least 10%, ascompared with an equivalent dose of placebo.

Typically, by the use of the present invention, the response of feelingsleepy and needing to make some effort to stay awake or very sleepy, asdetermined, for instance, in accordance with points 8 and 9 of theKarolinska 9 point scale is improved (ie. decreased) by between 1% and100%, more typically, by between 2% and 75%, most typically, by between4% and 60%, as compared with an equivalent dose of placebo.

Preferably, in use of the present invention as defined herein, thesleeptime awakenings, as for example determined by the Night diary ofthe Loughborough sleep log, may be decreased by 2-40%, typically, by10-35%, most typically by 15-30%, as compared with an equivalent dose ofplacebo. An especially preferred range is 15-40%. Preferably, in use ofthe present invention as defined herein, the sleeptime awakenings may bedecreased by more than 5%, more preferably by more than 10%, mostpreferably, by more than 15%, as compared with an equivalent dose ofplacebo.

Preferably, in use of the present invention as defined herein, sleepdisturbance index (SDI), as for instance determined by actimetry, may bedecreased by more than 5%, more preferably by more than 10%, mostpreferably by more than 15% as compared with an equivalent dose ofplacebo.

Preferably, in use of the present invention as defined herein, SDI maybe decreased by 5-30%, more typically 5-25%, most typically 10-20% ascompared with an equivalent dose of placebo. An especially preferredrange is 10-30%, more especially 10-25%.

Preferably, in use of the present invention as defined herein, time tosleep onset (TTSO) as, for instance, determined by actimetry may bedecreased by 540%, more typically 15-35%, most typically 20-30% ascompared with an equivalent dose of placebo. An especially preferredrange is 20-40%, more especially 20-35%.

Preferably, in use of the present invention as defined herein, the timeto sleep onset (TTSO) as compared with an equivalent dose of placebo isdecreased by at least 10%, more preferably by at least 15%, mostpreferably, by at least 20%.

Preferably, the quality of sleep experienced as felt after awakening isalso improved by the use of the present invention, typically the qualityof sleep is improved by 2-30%, more typically 5-30%, most typically10-20% as compared with an equivalent dose of placebo and as, forinstance, determined by the morning log of the Loughborough sleep log.Typically, in use of the present invention as defined herein, thequality of sleep is improved by at least 2%, more preferably at least5%, most preferably at least 10% as compared with an equivalent dose ofplacebo.

Preferably, in use of the present invention, the time to fall asleep asdetermined, for instance, by the Night diary of the Loughborough sleeplog is decreased by 140%, more typically 5-35%, most typically 10-30%.An especially preferred range is 10-40%, more especially 10-35%.Typically, in use of the present invention as defined here, the time tofall asleep as aforementioned is decreased by at least 2%, moretypically, by at least 5%, most typically by at least 10% as comparedwith an equivalent dose of placebo.

Preferably, by the use of the present invention, the response ofsleeping extremely well or very well, as determined, for instance, inaccordance with the morning log of the Loughborough sleep log, isimproved by at least 20%, more preferably, at least, 35%, mostpreferably at least 50%, as compared with an equivalent dose of placebo.

Preferably, by the use of the present invention, the response ofsleeping extremely well or very well, as determined, for instance, inaccordance with the morning log of the Loughborough sleep log, is foundfor at least 20% of individuals, more preferably, at least 25%, mostpreferably, at least 30%. For example over 35% of individuals had such aresponse.

Typically, by the use of the present invention, the response of sleepingextremely well or very well, as determined, for instance, in accordancewith the morning log of the Loughborough sleep log is improved bybetween 10% and 200%, most typically, by between 20% and 150%, moretypically by between 25% and 135% as compared with an equivalent dose ofplacebo. Typically, by the use of the present invention, the response ofsleeping extremely well or very well, as determined, for instance, inaccordance with the morning log of the Loughborough sleep log is foundfor between 25% and 100% of individuals, more typically, 30-80% mosttypically 35-70%. Especially preferred is the response in at leastbetween 35-60%, of individuals, more especially 35-45%.

It will be understood that references herein to “triprolidine” includethe compound(E)-2-[1-(4-methylphenyl-3-(1-pyrrolidinyl)-1-propenyl]pyridine as wellas salts thereof that are acceptable for administration to the humanbody. Acid addition salts may particularly be mentioned, including thehydrobromide and hydrochloride salts. The hydrochloride salt, i.e.triprolidine hydrochloride, is particularly preferred for use inaccordance with the invention. Solvates of triprolidine, notablyhydrates, e.g. monohydrates, and to the extent that triprolidine mayexist in polymorphic forms, all such polymorphs are within the scope ofthe invention.

The term “refreshed” as used herein means an individual waking refreshedor alert after a dose of triprolidine has been administered prior tosleep. In this context, the determination of whether an individual isfeeling “refreshed” may be made by a subjective test. An examplesubjective test is measuring the degree of alertness on, for instance,the Karolinska scale or the feeling of being refreshed as determined by,for instance, the Loughborough sleep log. Alternatively, refreshednessmay be based upon the inverse relationship between refreshedness andrelative levels of sleepiness as determined by the Karolinska scale.

By the term individual as referred to herein is meant any mammal orhuman.

The administration of the active ingredient in accordance with theinvention may be beneficial in that there is evidence that users feelmore refreshed upon awakening, which is not the case with othertreatments for sleep disorders, or indeed in the absence of anytreatment, and do not experience grogginess or a “hangover” effect afterthe required number of hours sleep. This too is surprising in view ofthe fact that such feelings have been reported in relation to otheractive ingredients which have a comparable mode of action to that oftriprolidine. Furthermore, there is no evidence that repeated use of theactive ingredient over the course of several days leads to any loss ofeffect.

The administration of the active ingredient in accordance with theinvention may also be beneficial in that it may decrease the timerequired for a user to fall asleep, which is surprising in view of thepreviously-reported studies on volunteers. In addition, the total periodof sleep may be increased and the incidence and duration of night-timewakenings experienced by the user may be reduced.

Although the active ingredient may be co-administered with anotherpharmacologically active agent, presently preferred formulations containtriprolidine as the sole active agent.

The active ingredient is preferably formulated in such a manner as tolead to non-sustained, substantially immediate release of the activeingredient, i.e. the formulation is preferably free of ingredientsintended or effective to prolong or sustain release of the activeingredient.

Administration of the active ingredient in accordance with the inventionmay be by a variety of routes. However, most commonly the activeingredient will be administered orally. An alternative mode ofadministration may be administration to the mucous membranes of thenasal passages. Further modes of administration are transdermal (e.g.using transdermal patches or bandages), rectal (e.g. as suppositories),optical, sub-lingual and pulmonary.

For oral administration, the active ingredient may be put up in avariety of dosage forms. Most commonly, the active ingredient will beformulated and administered as a tablet or the like. However,formulation as capsules, lozenges, drinks or as a syrup (solution orsuspension) may also be possible, as may other dosage forms such as oralsprays.

For nasal administration, the active ingredient may be formulated as asolution, emulsion or suspension and administered by means of a sprayusing a suitable delivery device. Alternatively, for pulmonaryadministration, the active ingredient may be administered as a powder,either from a pressurised aerosol delivery device or from a so-calleddry powder inhaler.

For formulation in the presently preferred form, i.e. as a tablet, theactive ingredient will generally be combined with various excipients ina manner which is known Per se. In particular, the tablet will generallycomprise one or more diluents or bulking agents. A diluent may alsoserve as a disintegrant, or the formulation may incorporate a separatedisintegrant. A lubricant may also be included to facilitate release ofthe formed tablets from the tabletting dies of a tablet forming machine.

Thus, according to a further aspect of the invention, there is provideda tablet for enabling an individual to wake refreshed after sleeping,which tablet comprises triprolidine as sole active ingredient inadmixture with one or more diluents and/or a disintegrant, the tabletcomprising more than 0.01 mg and less than 4.9 mg triprolidine.

As noted above, the formulation may incorporate one diluent or bulkingagent, or more than one. Formulations are preferred which contain blendsof two or more diluents, one of which may also serve as a disintegrant.

Preferred materials for the diluent or bulking agents includepolysaccharides and derivatives thereof, and saccharides.

Polysaccharides which may be used include starch, e.g. maize starch,cellulose, e.g. powdered cellulose and microcrystalline cellulose,water-insoluble modified starches, e.g. sodium carboxymethyl starch,water-insoluble cellulose derivatives, e.g. croscarmellose sodium(cross-linked sodium carboxymethyl cellulose), cross-linkedpolyvinylpyrrolidone and alginic acid.

Another preferred form of diluent is a saccharide. Suitable saccharidesinclude, for example, sucrose, lactose, dextrose, sorbitol, mannitol,xylitol and maltodextrin. Lactose and sucrose are preferred saccharides.Lactose is especially preferred. Saccharide diluents may also bebeneficial in terms of modifying the taste of the formulation.

Particularly preferred diluents are dicalcium phosphate,microcrystalline cellulose, e.g. the products sold as Avicel PH-101 andAvicel PH-102 (Avicel is a Trade Mark) by the FMC Corporation ofPhiladelphia, Pa., USA, and lactose.

Another preferred disintegrant is a croscarmellose sodium, for examplethe product sold as Ac-Di-Sol (Ac-Di-Sol is a Trade Mark) by the FMCCorporation. This product, when included in the formulation, also servesas a disintegrant.

The disintegrant has the effect of causing the tablet composition todisintegrate under the conditions found in the gastro-intestinal tract.Apart from croscarmellose sodium, examples of disintegrants include oneor more of wheat starch, maize starch, potato starch, sodium starchglycolate, low-substituted hydroxypropyl cellulose, alginic acid,cross-linked polyvinylpyrrolidone and magnesium aluminium silicate.Preferred disintegrants are those which swell on the action of waterthus causing the ingredients in the tablet to be pushed apart and outinto the aqueous disintegration medium. The preferred disintegrant iscroscarmellose sodium. The disintegrant is present at an effectivedisintegrating amount, for example up to 25% by weight of thecomposition, more preferably 1-25% w/w, further preferably 3-20% w/w andmost preferably 5-15% by weight of the composition.

Particularly preferred compositions, in a particular tabletcompositions, include a blend of a cellulosic diluent, a saccharidediluent and a disintegrant. The preferred cellulosic diluent ismicrocrystalline cellulose, the preferred saccharide is lactose and thepreferred disintegrant is croscarmellose sodium.

A preferred formulation, in particular a tablet formulation, comprisesthe cellulosic diluent, the saccharide diluent and the disintegrant inthe ratio of 0.01-10 parts by weight of cellulosic diluent, 0.01-10parts by weight of saccharide diluent to 1 part by weight ofdisintegrant. More preferably, the formulation contains 2-5 parts byweight of cellulosic diluent per part by weight of disintegrant, and 4to 7 parts by weight of saccharide diluent per part by weight ofdisintegrant.

The diluents and/or disintegrant are preferably incorporated into thecompositions in finely divided (powder) form.

The diluents and disintegrant preferably together constitute in excessof 80% w/w of the tablet formulation, more preferably in excess of 90%w/w, and most preferably in excess of 94% w/w.

The lubricant may be, for example, stearic acid, a metallic stearate, apolyethylene glycol of molecular weight of 4,000 or more, or purifiedtalc. The preferred lubricant is a metallic stearate, particularlymagnesium stearate, which may be present in the formulation atrelatively low levels, typically less than 1% or 0.5% by weight.

It has been found to be particularly advantageous for the tabletformulation to be formed with a coating, preferably a sugar coating orfilm coating process, more preferably a film coating comprising ahydrophilic polymer, particularly a cellulose derivative such as amethylated cellulose derivative, e.g. hydroxyethylmethylcellulose and,particularly, hydroxypropylmethylcellulose.

The coating may also comprise an inorganic filler material, mostpreferably french chalk, to enhance the physical properties of thecoating and prevent cracking etc, and also a pigment, e.g. a titaniumdioxide pigment dispersion.

It has been found that, in addition to improving the appearance of thetablet and acting as a barrier to ingress of moisture, the film coatingis also effective in masking the taste of the active ingredient.

The tablet formulation may be prepared by a process involving dryblending or wet or dry granulation. However, it is preferred to use amanufacturing method which involves direct compression into a tabletwithout an intermediate, e.g. a wet or dry granulation, stage.

The formulation may be made by dry mixing the active ingredient with theother ingredients, e.g. the lubricant and diluents and disintegrant,e.g. in a powder blending machine. It is particularly preferred that theactive ingredient is dispersed by progressive dilution with agitation ina proportion, e.g. about one-half, of the excipients so as to achieveeven distribution of the active ingredient in the excipients, and thento add the remainder of the excipients with further agitation andmixing. The mixture may then be compressed in a tablet forming machineand a coating, preferably a sugar coat or a film coat may then beapplied to the tablets so formed by spraying the tablets with a solutionor suspension of the coating-forming ingredients while the tablets aretumbled.

Such a direct tablet compression manufacturing method has been found tobe beneficial in that it avoids problems attributable to crystal growthand changes in morphology which might occur in a wet granulationprocess.

Other, currently less preferred, dosage forms may be prepared in amanner which is generally known per se. For example, syrups may beprepared by dissolving or suspending the active ingredient in a liquidvehicle, e.g. water, optionally with suspending agents or the like, e.g.cellulose derivatives, gums etc.

For administration by inhalation, via nose or mouth, the formulationsmay be formulated with a compressed gas or liquified gas propellant,e.g. any conventionally used propellant such as a chlorofluorocarbon,hydrofluorocarbon, compressed hydrocarbon, nitrogen etc. Alternatively,the active ingredient may be formulated as a dry powder, generally inadmixture with a diluent such as crystalline lactose.

The amount of active ingredient to be administered in a single dose mayvary quite widely, depending inter alia on the desired effect and themode of administration. However, a formulation for oral administration,e.g. a tablet, will generally contain at least 0.01 and up to 20 mg ofactive ingredient, more commonly at least 0.5 mg and less than 10 mg ofactive ingredient, most commonly no more than 5 mg, e.g. 1.25 or 2.5 mg.Doses of formulations for administration by nasal and sub-lingualadministration, which would be expected to deliver the active ingredientmore quickly and efficiently, may contain less active ingredient, e.g.between 0.1 and 1.0 mg, e.g. about 0.5 mg and generally at a level of20% of the oral dose levels mentioned herein. Preferably, such nasal andsub-lingual formulations contain active ingredient in the range 0.01-2.5mg, more preferably, 0.05-1.0 mg and most preferably, 0.1-0.5 mg.

In general, the desired dose (which may comprise one or more unit doses,e.g. one or two tablets or the like) will be taken by a user prior tothe desired time at which it is desired for the composition to takeeffect. Most commonly, the dose will be taken at night-time, i.e. priorto the user sleeping through hours of darkness. Typically, the dose maythus be taken after 8 pm in the evening or later, say after 9 pm orafter 10 pm. Typically, it may be recommended that the user take thecomposition between 0 more commonly 1 minute and 2 hours prior to thetime at which he or she wishes to fall asleep. Most commonly, thecomposition may be taken about 10 to 30 minutes prior to that time. Inaddition, however, the active ingredient may be effective, particularlyat lower doses, in restoring sleep, e.g. in the event of night-timewaking.

Preferably, the use of triprolidine in any aspect of the invention asdefined herein is its use as active ingredient. Preferably, thetriprolidine in any aspect of the invention defined herein is in theform of a non-toxic effective dose, preferably, suitable for any givenmammal or human and determined in accordance with age and weight.

Preferably, to obtain the benefits on waking or otherwise as definedherein, the active ingredient of triprolidine administered beforesleeptime is less than 10 mg, typically less than 5 mg, more preferably,less than 4.5 mg, most preferably less than 4.0 mg. Especially preferredis a dose as aforesaid of less than 3.5 mg and most especially preferredis a dose of less than 3.0 mg. Typically, the dose of triprolidine isbetween 0.01 and 10.0 mg, preferably, between 0.01 and 4.9 mg, morepreferably, between 0.1 and 4.5 mg, most preferably between 0.5 and 4mg. Especially preferred is a dose of between 1 and 3.5 mg and moreespecially a dose of between 2.0 and 3.0 mg. Most especially preferredis a dose as aforesaid of about 2.5 mg or 1.25 mg. Preferably, the abovedosage levels are based on triprolidine hydrochloride monohydrate andamounts of other salts or hydrates should be varied accordingly todeliver the equivalent amount of active ingredient.

In the formulations of the present invention, the triprolidine may be inany suitable release form such as a slow release, sustained release,immediate release or uncontrolled release form. The formulation may alsobe in any one or more of the following delivery forms:—

-   Pastilles-   lozenge-   chewable tablets-   fondant-fill tablets-   coated or uncoated tablets-   sub-lingual tablets-   fast-melt tablets-   hot or cold drinks-   syrups-   drops-   emulsions-   dry powder-   suspension-   transdermal patch-   suppository-   sub-lingual and nasal sprays

Preferably, the dose of the triprolidine in accordance with theinvention may be taken by an individual before it is desired to go tosleep (sleeptime), preferably less than two hours before sleeptime, morepreferably, less than one hour before sleeptime, most preferably, lessthan 20 minutes before sleeptime. Especially preferred is to take thedose of triprolidine less than 15 minutes before sleeptime.

Preferably, the dose of triprolidine is less than 4 doses per day (24hour period), more preferably, less than 3 doses per day, mostpreferably less than 2 doses per day. Especially, preferred is 1 doseper day.

The packaging of the invention as defined herein may be in any suitableform such as, for example, a blister pack, bottle, tamper-proofcontainer, sachet, box, etc. The packaging of the invention may beassociated with instructions for any of the features or preferredfeatures of the invention as defined herein.

For the avoidance of doubt, reference to the “use of the presentinvention” herein should be taken to include “the method of theinvention”, and “use of a pharmaceutical formulation” as well as use ofthe present invention per se.

Advantageously, the use of triprolidine in the present invention resultsin a reduced hangover or morning grogginess effect as compared withother sleep aids or sleep disorder remedies. More advantageously, theuse of triprolidine in the present invention provides an improved degreeof refreshedness or more refreshed feeling upon waking as determined bythe Loughborough sleep log or Karolinska scale and as compared withplacebo.

For the avoidance of doubt, reference to quantities of triprolidineherein should be taken as references to quantities of the hydrochloridemono hydrate (HCl. H₂O) form. However, it should be appreciated that theinvention extends to other forms, including all pharmaceutically activesalts and hydrates thereof.

The term refreshed as used herein may be substituted by any termselected from alert, invigorated, revitalised, re-energised, recharged,rejuvenated, attentive, awake or words having the like effect orequivalent general meaning and the term refreshedness may also besubstituted by the grammatical equivalent thereof from the wordsaforesaid. In addition, the term alert as used herein can be substitutedby any of the above alternative terms.

Examples of tablet formulations which may be used in the invention areas follows:

EXAMPLE 1 5 mg Tablet

Parts by weight/ Ingredients mg per tablet 1 Triprolidine hydrochlorideBP 5 2 Microcrystalline cellulose 102 87.5 3 Lactose 137.5 4 Magnesiumstearate BP 1 5 Croscarmellose sodium 25 6 Opaspray White M-1-7111B 1.087 French chalk for tablets 0.65 8 Hydroxypropylmethylcellulose 2910 USP606 3.27Method

-   (a) Triprolidine hydrochloride (1) was mixed with approximately    one-half of the components (2)-(5) and thoroughly mixed. The    remainder of components (2)-(5) were added and mixing continued to    achieve uniform distribution of the active ingredient in the    mixture.-   (b) The mixture was compressed to form tablets, each containing 5 mg    of active ingredient, in a tablet forming machine.-   (c) The tablets were film-coated by spraying with an aqueous    suspension of components (6)-(8) containing 15% solids while being    tumbled, followed by drying.

EXAMPLE 2 2.5 mg Tablet

Parts by weight/ Ingredients mg per tablet 1 Triprolidine hydrochlorideBP 2.5 2 Microcrystalline cellulose 102 87.5 3 Lactose 137.5 4 Magnesiumstearate BP 1 5 Croscarmellose sodium 25 6 Opaspray White M-1-7111B 1.087 French chalk for tablets 0.65 8 Hydroxypropylmethylcellulose 2910 USP606 3.27Method

Prepared by a method analogous to Example 1.

EXAMPLE 3

Example 3 was produced in accordance with the following composition andconstituted the trial formulation unless otherwise mentionedhereinafter. Patients received one tablet for the 2.5 mg dose and twotablets for the 5.0 mg dose. Name of Ingredient mg/tablet 1.Triprolidine HCl.H₂O 2.5 2. Micro-crystalline Cellulose 29.0 3. LactoseH₂O 60.0 4. Magnesium Stearate 1.0 5. Croscarmellose Sodium 10.0Method

Example 3 was prepared by the method analogous to example 1 (a) and (b)above.

EXAMPLE 4

Example 4 was produced in accordance with the following composition andmethod and provides an example of an alternative fast melt formulation.

Triprolidine Fast Melt Tablets (2.5 mg) Ingredient Functionality % w/vTriprolidine Hydrochloride Active 2.5 mg Mannitol Filler/sweetener 400mg Sodium Croscarmellose Disintegrant 25 mg Aspartame Sweetener 20 mgPrecipitated Silica Flow aid 10 mg Flavour Flavour qs Magnesium StearateLubricant 2.5 mg Total 460 mg

Blend the triprolidine, manitol, aspartame, sodium croscarmellose,silica and flavouring for 20 minutes in a suitable blender. Add themagnesium stearate and further blend for 5 mins. Compress the blend intotablets of weight 460 mg.

Examples 5-7 illustrate further formulations for the triprolidine of thepresent invention.

EXAMPLE 5

Triprolidine Sugar Free Syrup (2.5 mg/5 ml) Ingredient Functionality %w/v Triprolidine Hydrochloride Active 0.05 g Purified Water Solubilizer50% Natrosol 250 HX Thickener 0.6 Glycerin Sugar free diluent 20%Lycasin 80/55 Sugar free diluent 20% Acesulfame K Sweetener 0.075Domiphen Bromide Preservative 0.01 Flavour Flavour qs Colour Colour qsPurified Water to 100% 

Dissolve the triprolidine in purified water in a suitable vessel. Stiruntil a clear solution is produced. In a separate vessel add theglycerin and the lycasin, heat to 40° C. Slowly add the Natrosol.Recirculate through an in-line Silverson® with a 2 mm screen until allthe lumps have disappeared and the bulk is uniform.

Add the Natrosol solution to the triprolidine solution via the in-lineSilverson®. Add with stirring the Domiphen Bromide, Acesulfame K,flavour and Colour. Stir until a homogenous mix is produced and passthrough a 60 mesh sieve into bulk containers.

EXAMPLE 6

Triprolidine Hot Drink (2.5 mg/sachet) Ingredient Functionalitymg/sachet Triprolidine Hydrochloride Active 2.5 Acesulfame PottasiumSweetener 12.5 Aspartame Sweetener 12.5 Malted milk Flavour Flavour 200French Vanilla Flavour Flavour 225 Lactose Filler 2547.5 Purified WaterGranulating solution qs Total 3000 mg

The triprolidine is dissolved in purified water. Lactose, aspartame andacesulfame are sieved and dry mixed before being granulated with thepreviously prepared triprolidine solution. The granules are fluid beddried, sieved and blended with the flavours.

EXAMPLE 7

Triprolidine Pastille (2.5 mg) Ingredient Functionality mg/pastilleTriprolidine hydrochloride Active 2.5 Gum Arabic Natural gum 986Maltitol syrup sugar free diluent 859.5 Glycerin sugar free diluent 81Citric Acid pH adjuster/flavour 39 enhancer Flavour Flavour 23Acesulfame K Sweetener 2 Hibiscus Extract Flavour 4 Miglyol Oil - 866surfactant 4 Water 299 Total 2300 mg

The gum is dispersed in water (95° C.), with stirring. Maltitol syrupand glycerin are mixed and pumped in to the pre-cooker at 126° C. Thegum solution is pumped into the maltitol syrup solution and mixed. Thetriprolidine, flavours and colours are added to the mixture.

The pastille mixture is pumped from the dispenser to the depositinghopper to form the pastilles in the starch mould boards. The pastillesare left to gel for 6-8 days.

Clinical Trial

The efficacy of triprolidine in enabling a patient to feel refreshed oralert upon waking after taking triprolidine prior to sleeptime wasinvestigated using patients with a history of sleep disorders andutilising triprolidine prepared in accordance with example 3.

The study herein utilised the following determination methods:—

-   (a) Karolinska scale as defined in: Int. J. Neuroscience 52 29-37    (1990); and validation: Sleep 17 (3) 236-41 (1994)-   (b) Loughborough Sleep log as defined in: Sleep 17 (2)146-159    (1994); and Sleep 18 (2) 127-134 (1995)-   (c) Actimetry—AW4 actimeters (Cambridge Neurotechnology) were worn    continuously throughout the study. A button was pressed at night    when the subject desired to go to sleep and again in the morning    upon waking. The results of the actimeter study were analysed in the    manner defined by Home et al (Sleep, 17(2); 146-159).

SDI % was calculated as follows:—${SDI} = {\frac{{Number}\quad{of}\quad 30\quad{second}\quad{epochs}\quad{with}\quad{movement}}{{Number}\quad{of}\quad 30\quad{second}\quad{epochs}\quad{from}\quad{total}\quad{time}\quad{spent}\quad{in}\quad{bed}} \times 100}$

This is the measure of:

-   -   1. The length of time it took to fall asleep    -   2. Any awakenings throughout the sleep period    -   Expressed as a % of total time spent in bed.        Study Objectives    -   To evaluate the effects of two doses of triprolidine compared        with placebo.        Study Design

A multiple-dose, placebo-controlled, parallel-group, double-blind,randomised study investigating the effects of 2.5 mg and 5 mgtriprolidine in patients with temporary sleep disturbance.

Male and Female candidates aged 18 years and above were recruited to oneof five research centres by means of local advertising. Candidates werescreened by means of a telephone questionnaire and selected candidatesinvited for interview at the research centre. Key inclusion criteriaused to select candidates for the study were:

-   -   A record of poor sleep at least 2 nights per week    -   A record of poor sleep for at least 1 week but not more than 3        months    -   Sleep disturbance not caused by underlying disease    -   No excess use of alcohol or drugs    -   Sleep disturbance affected daytime functioning

The candidates came to the research centre on Thursday or Friday andwere fitted with a wrist actimeter (AW4 from Cambridge Technology) toestablish a baseline measure for SDI and were provided with diary cardsto record subjective assessments for the Loughborough Sleep Log and theKarolinska Sleepiness Scale. They returned to the investigational siteon the Monday and were issued with the study compositions (2.5 mgtriprolidine, 5 mg triprolidine or placebo). The investigator telephoneda central randomisation centre where the subject was randomised to aparticular treatment group using a dynamic balanced randomisationalgorithm. The subject was given three doses of their allocated studymedication and instructed to take a single dose of two tablets 20minutes before they intended to go to sleep on three consecutiveevenings, commencing that evening. The diary cards for the LoughboroughSleep Log and Karolinska Sleepiness Scale were asked to be completed onwaking.

The candidates returned to the research centre on the following Friday.

Parameters Evaluated

Candidates were required to complete a questionnaire 15 minutes afterawaking on the feeling of refreshedness assessed on a 5-point scale, theLoughborough sleep log.

A daytime sleepiness assessment was also made 20 minutes, 2 hours and 4hours after awaking on the Karolinska 9-point scale, ie. the sleepinessscale.

Results

198 candidates completed the study, of whom 178 provided evaluable data.(61 placebo, 60 on 2.5 mg triprolidine and 57 on 5 mg triprolidine. Thesubjects on 2.5 mg dose took one tablet and placebo those on 5 mg dosetook 2×2.5 mg tablets. The subjects on placebo took a dose to match theactive treatments (2 tablets).

Key results were as follows:

-   -   There was evidence that there was a lack of daytime sleepiness        associated with those patients who took either dose of        triprolidine    -   The SDI was reduced for both treatments as compared with placebo        on every treatment night    -   The sleep latency onset was reduced for both treatments as        compared with placebo on every treatment night

The following results were obtained for patients taking 2.5 mgtriprolidine. For the mean of the 3 nights:

-   -   15 minutes after waking, patients taking triprolidine recorded        feeling more refreshed than those on placebo, as determined by        the Loughborough sleep log(p<0.05).    -   There were a greater percentage of people on 2.5 mg triprolidine        who, on waking were feeling alert, very alert or extremely alert        than those on placebo as measured by the Karolinska log.    -   There was a lower percentage of people on 2.5 mg triprolidine        who, on waking were feeling sleepy, and needing to make some        effort or very sleepy, needing to make a great effort to keep        awake than those on placebo as measured by the Karolinska log.    -   There was no evidence of residual hangover effects/morning        grogginess from the drug.    -   The SDI was significantly reduced compared to those on placebo        (p<0.01).    -   The sleep latency onset was reduced as compared to those on        placebo (p<0.05).

Further analyses show the advantageous effects of triprolidine inrelation to the degree of refreshedness on waking.

The study design used 3 groups. On average, the number of individuals ineach of the 3 groups (placebo, 2.5 mg triprolidine and 5 mgtriprolidine) was 60±10 patients.

In the trial, patients were tested during a seven day period and theresults have been analysed for a mean of three days in the middle ofthis period. The effects of triprolidine at dose level 2.5 mg and 5.0 mgare compared with placebo in table 1. TABLE 1 Datasets (a) to (g) - MainAnalyses Placebo 2.5 mg 5 mg Mean Mean Mean (a) SDI (%) (Sleep latencyonset and Mon 13.19 11.33 11.72 Quality of sleep) Tues 14.58 12.15 12.71(Actimeter) Wed 14.46 11.2 11.81 Mean of 3 14.26 11.56 12.23 (b) TTSO(min) (Time to Sleep onset) Mon 20.75 16.22 16.16 (Actimeter) Tues 22.2915.62 17.88 Wed 20.26 14.8 16.36 Mean of 3 22.16 15.53 16.93 (c) 15 minsafter awaking (1 - very refreshed Mon 3.41 3.33 3.72 5 - very tired)Tues 3.46 3.23 3.56 (Loughborough sleep log) Wed 3.42 3.18 3.54 Mean of3 3.45 3.24 3.59 (d) last night I slept 1 - extremely well, Mon 3.2 2.672.49 5 - extremely badly) Tues 3.06 2.71 2.93 (Loughborough sleep log)Wed 3.02 2.81 2.64 Mean of 3 3.11 2.73 2.69 (e) time to fall asleep(min) (Loughborough sleep log) Mon 33.61 23.67 22.02 Tues 29.73 24.4432.08 Wed 28.35 20.95 24.24 Mean of 3 30.98 23.93 26.5 (f) no of timeswoke up (Loughborough sleep log) Mon 1.9 1.18 1.49 Tues 1.61 1.37 1.42Wed 1.43 1.11 1.39 Mean of 3 1.71 1.22 1.42Statistical Analysis

Generally the treatment groups were well balanced in terms of thedemographic data. Unless otherwise mentioned all group data was analysedusing ANOVA. In two cases, namely, how the patient felt 15 minutes afterawakening in the Loughborough Sleep Log and the Karolinska SleepinessScale at 20 minutes, the two variables were analysed using ANCOVA byincluding the weekend and the mean of Friday/Saturday/Sunday night as acovariate. The method was a closed test procedure (Williams' test). Eachof the tests were to be conducted at the 5% level. The analysis of thesecondary endpoints was similarly conducted using the Student's t-testson parameter estimates taken from the analysis of variance modelpresented above.

The following is a copy of the “Loughborough sleep log questionnaire”which was used by patients in the study and provided the data fordatasets a and b in table 1.

“Loughborough Sleep Log” Questionnaire

This will be completed 15 minutes after waking.

Bedtime Log

-   I went to bed at: . . . I turned out the lights at: . . .-   The windows are: shut . . .    -   Not shut . . .        Morning Log-   I woke up at . . . this morning I got out of bed at . . . this    morning-   15 minutes after waking I felt: Last night I slept:    -   a) very refreshed . . . a) extremely well . . .    -   b) refreshed . . . b) very well . . .    -   c) neither refreshed nor tired . . . c) fairly well . . .    -   d) tired . . . d) rather badly . . .    -   e) very tired . . . e) extremely badly . . .        Night Diary-   During the night the windows were left: opened . . .    -   shut . . .-   During the night the secondary glazing was left: opened . . .    -   shut . . .-   During the night my partner slept in: the same bed as me . . . a    different bed to me.-   As far as I can remember, it took me . . . minutes to fall asleep    last night-   As far as I can remember, I woke up . . . times last night-   Please note the details of any awakenings you can remember in the    table below.-   Time Length of time awake (mins) Reason for awakening.”

Table 2 shows additional data in connection with data set (a) showingthe improvement in refreshed responses at the 2.5 mg dosage oftriprolidine hydrochloride monohydrate. TABLE 2 Loughborough Sleep Log:Awoke Very Refreshed or Refreshed Responses Day of Testing MondayTuesday Wednesday Dose N % n % n % Placebo 10 15.2 10 16.4 11 18.3 2.5mg TRP.HCl.H₂O 14 23 14 23 16 25.8   5 mg TRP.HCl.H₂O 7 11.5 5 8.2 914.8

Similarly, table 3 shows corresponding additional data in connectionwith data set (b). TABLE 3 Loughborough Sleep Log: Last Night I SleptExtremely Well or Very Well Responses Day of Testing Monday TuesdayWednesday Dose N % n % n % Placebo 11 18 12 22.2 13 24.1 2.5 mgTRP.HCl.H₂O 24 41.4 23 41.8 22 37.9   5 mg TRP.HCl.H₂O 30 50.9 17 28.824 39.3

Karolinska's sleepiness scale is set out below and the results forplacebo, 2.5 and 5.0 mg doses of triprolidine are shown in tables 4 and5. Table 4 relates to the number of individuals experiencing scales 1, 2or 3 on the Karolinska scale and table 5 relates to the number ofindividuals experiencing scales 8 and 9.

Karolinska Sleepiness Scale

This will be completed 20 minutes after awakening and then at 2 hoursand 4 hours following the first assessment on days 5, 6, 7 and 8.

-   -   1. Extremely alert    -   2. Very alert    -   3. Alert    -   4. Rather alert    -   5. Neither sleepy or alert    -   6. Some signs of sleepiness    -   7. Sleepy but no effort to keep awake    -   8. Sleepy, some effort to keep awake

9. Very sleepy, Great effort to stay awake, fighting sleep TABLE 4Karolinska 9-point scale (a) I feel extremely alert, very alert or alertDay of Testing Monday Tuesday Wednesday Dose n % n % n % Placebo 9 13.614 23.0 11 17.2 2.5 mg TRP.HCI.H₂O 13 21.3 13 21.3 13 21.0   5 mgTRP.HCl.H₂O 4 6.3 6 9.5 11 17.5

TABLE 5 (b) I feel (i) sleepy, [and need to make] some effort or (ii)very sleepy, a great effort to keep awake Day of Testing Monday TuesdayWednesday Dose n % n % n % Placebo 8 12.1 10 16.4 9 14.1 2.5 mgTRP.HCl.H₂O 7 11.5 8 13.1 4 6.5   5 mg TRP.HCl.H₂O 8 12.5 11 17.5 8 12.7

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

All of the features disclosed in this specification (including anyaccompanying claims, abstract and drawings), and/or all of the steps ofany method or process so disclosed, may be combined in any combination,except combinations where at least some of such features and/or stepsare mutually exclusive.

Each feature disclosed in this specification (including any accompanyingclaims, abstract and drawings), may be replaced by alternative featuresserving the same, equivalent or similar purpose, unless expressly statedotherwise. Thus, unless expressly stated otherwise, each featuredisclosed is one example only of a generic series of equivalent orsimilar features.

The invention is not restricted to the details of the foregoingembodiment(s). The invention extends to any novel one, or any novelcombination, of the features disclosed in this specification (includingany accompanying claims, abstract and drawings), or to any novel one, orany novel combination, of the steps of any method or process sodisclosed.

1. The use of triprolidine or a salt or hydrate thereof as activeingredient of an aid to waking refreshed after sleeping.
 2. The use oftriprolidine or a salt or hydrate thereof as active ingredient in thepreparation of a composition for enabling an individual to wakerefreshed after sleeping.
 3. The use of triprolidine or a salt orhydrate thereof as active ingredient in the preparation of a medicamentfor enabling an individual to wake refreshed after sleeping.
 4. The useof triprolidine or a salt or hydrate thereof in the preparation of asleep aid which also enables an individual to wake refreshed aftersleeping.
 5. The use of triprolidine or a salt or hydrate thereof asactive ingredient of a sleep aid which also enables an individual towake refreshed after sleeping.
 6. The use of triprolidine or a salt orhydrate thereof as active ingredient in the preparation of a medicamentfor the treatment or prevention of a sleep disorder which also enablesan individual to wake refreshed after sleeping.
 7. Use of triprolidineas active ingredient in the manufacture of a composition for thetreatment of sleep disorders.
 8. The use of triprolidine as activeingredient in the manufacture of a composition for inducing, prolongingand/or enhancing sleep and/or sleep quality.
 9. A method for thetreatment or prevention of grogginess, drowsiness or lethargy on wakingfrom sleep in a mammal comprising the administration to the mammal inneed thereof of a non-toxic effective dose of triprolidine or a salt orhydrate thereof prior to the desired sleeping time.
 10. A method forenabling an individual to wake refreshed after sleeping comprising theadministration to the individual in need thereof and prior to thedesired sleeping time of a non-toxic effective dose of triprolidine or asalt or hydrate thereof.
 11. A method for aiding an individual's sleepand for also enabling the individual to subsequently wake refreshedafter sleeping comprising the administration to the individual in needthereof and prior to the desired sleeping time of a non-toxic effectivedose of triprolidine or a salt or hydrate thereof.
 12. A method oftreating sleep of a person suffering from a sleep disorder, which methodcomprises administration of an effective dose of triprolidine as activeingredient to such a person.
 13. A method for inducing, prolongingand/or enhancing sleep, which method comprises administration of aneffective dose of triprolidine as active ingredient to a person desirousof achieving sleep.
 14. A waking refreshed aid comprising triprolidineor a salt or hydrate thereof as active ingredient in association with apharmaceutically acceptable carrier therefor and instructions foradministration thereof at or just before the desired sleeping time. 15.A pharmaceutical formulation for the treatment or prevention ofgrogginess, drowsiness or lethargy on waking after sleeping, comprisingtriprolidine or a salt or hydrate thereof as active ingredient inassociation with a pharmaceutically acceptable carrier therefor andinstructions for administration thereof at or just before the desiredsleeping time.
 16. A pharmaceutical formulation for enabling anindividual to wake more refreshed after sleeping, comprisingtriprolidine or a salt or hydrate thereof as active ingredient inassociation with a pharmaceutically acceptable carrier therefor andinstructions for administration thereof at or just before the desiredsleeping time.
 17. The use as claimed in claim 1, wherein the dose oftriprolidine administered to the user prior to sleeptime is between 0.01mg and 20 mg.
 18. The use as claimed in claim 1, wherein the dose oftriprolidine administered to the user before sleeptime is up to 20 mg.19. The method as claimed in claim 9, wherein the dose of activeingredient of triprolidine administered is between 0.01 and 20 mg. 20.The method as claimed in claim 9 wherein the dose of active ingredientof triprolidine administered is up to 20 mg.
 21. The pharmaceuticalformulation as claimed in claim 15, wherein the instructions foradministration instruct a single dose of the active ingredient oftriprolidine of up to 20 mg prior to sleeptime.
 22. The pharmaceuticalformulation as claimed in claim 15, wherein the instructions foradministration instruct a single dose of the active ingredient oftriprolidine of between 0.01 and 20 mg prior to sleeptime.
 23. A wakingrefreshed aid as claimed in claim 14, wherein the instructions foradministration instruct a single dose of the active ingredient of up to20 mg prior to sleeptime.
 24. A waking refreshed aid as claimed in claim14, wherein the instructions for administration instruct a single doseof the active ingredient of triprolidine of between 0.01 and 20 mg priorto sleeptime.
 25. A method as claimed in claim 9, wherein thetriprolidine is in the form of triprolidine hydrochloride.
 26. A methodas claimed in claim 9, wherein the person is suffering from a sleepdisorder.
 27. A method as claimed in claim 9, wherein the person is notsuffering from a sleep disorder but is desirous of achieving a feelingof waking refreshed upon waking.
 28. A method as claimed in claim 9,wherein the active ingredient is administered orally, nasally,optically, rectally, pulmonarily, transdermally or sub-lingually.
 29. Amethod as claimed in claim 9, wherein the active ingredient isadministered in the form of a tablet, capsule, drink, lozenge, drops,emulsion, dry powder, suspension, pastille, patch, suppository, syrup,sub-lingual spray or nasal spray.
 30. A method as claimed in claim 9,wherein the active ingredient is administered to the mucous membranes ofthe nasal cavity.
 31. A method as claimed in claim 9, wherein the activeingredient is administered as a solution or suspension spray or as apowder.
 32. A method as claimed in claim 9 in which the activeingredient is administered between 1 minute and 2 hours prior tosleeptime.
 33. Use as claimed in claim 1, wherein the triprolidine is inthe form of triprolidine hydrochloride.
 34. Use as claimed in claim 1,wherein the composition is for oral administration.
 35. Use as claimedin claim 1, wherein the composition is in the form of a tablet, capsule,drink, lozenge, drops, emulsion, dry powder, suspension, pastille,patch, suppository, syrup, sub-lingual spray or nasal spray.
 36. Use asclaimed in claim 1, wherein the composition is for administration to themucous membranes of the nasal cavity.
 37. Use as claimed in claim 1,wherein the composition is a solution or suspension or a powder.
 38. Theuse as claimed in claim 1, wherein the triprolidine forms the activeingredient of a formulation which contains a blend of two or morediluents, one of which may also serve as a disintegrant.
 39. The use asclaimed in claim 1, wherein the triprolidine forms the active ingredientof a formulation, which comprises a saccharide diluent.
 40. The use asclaimed in claim 39, wherein the triprolidine formulation furthercomprises a disintegrant.
 41. The use as claimed in claim 40, whereinthe triprolidine formulation further comprises the saccharide diluentand the disintegrant in the ratio of 1-10 parts by weight saccharidediluent to 1 part by weight of disintegrant.
 42. The use as claimed inclaim 40, wherein the saccharide diluent is lactose, and thedisintegrant is croscarmellose sodium.
 43. The use as claimed in claim38, wherein the triprolidine formulation further comprises a lubricant.44. The use as claimed in claim 43, wherein the lubricant is magnesiumstearate.
 45. The use as claimed in claim 38, wherein the triprolidineformulation is formed with a coating of a hydrophilic polymer.
 46. Theuse as claimed in claim 45, wherein the hydrophilic polymer is amethylated cellulose derivative.
 47. The use as claimed in claim 38,which is free of ingredients intended or effective to sustain or prolongrelease of the active ingredient.
 48. A method of manufacturing aformulation as claimed in claim 38, which involves direct compression ofthe ingredients into a tablet without an intermediate granulation stage.49. The uses of triprolidine as hereinbefore described and withreference to the examples.
 50. The methods for the treatment ofgrogginess as hereinbefore described and with reference to the examples.51. The tablets as hereinbefore described and with reference to theexamples.
 52. The pharmaceutical formulations as hereinbefore describedand with reference to the examples.
 53. The waking refreshed aids ashereinbefore described and with reference to the examples.
 54. Themethod for enabling an individual to wake refreshed after sleeping ashereinbefore described and with reference to the examples.
 55. A wakingrefreshed aid as hereinbefore described and with reference to theexamples.
 56. A pharmaceutical formulation as hereinbefore described andwith reference to the examples.
 57. Use of triprolidine as activeingredient in the manufacture of a composition for the treatment ofsleep disorders as hereinbefore described and with reference to theexamples.
 58. The use of triprolidine as active ingredient in themanufacture of a composition for inducing, prolonging and/or enhancingsleep as hereinbefore described and with reference to the examples. 59.A method of treating sleep of a person suffering from a sleep disorder,which method comprises administration of an effective dose oftriprolidine as active ingredient to such a person as hereinbeforedescribed and with reference to the examples.
 60. A method for inducing,prolonging and/or enhancing sleep, which method comprises administrationof an effective dose of triprolidine as active ingredient to a persondesirous of achieving sleep as hereinbefore described and with referenceto the examples.